Process for producing 4-substituted 1, 2-diaryl-3, 5-dioxo pyrazolidines



Patented Dec. 11, 1956 known method which is described e. g. in Ber., 1940, 73,

2373380 822, has the disadvantage that the final yield is rather low.

4.S S 1 U ED 12. Also, it is usually necessary to prepare pure alkylhalo- )A I Z% E-3 L S I )%RAZOLEINES genide, e. g. l-bromo-n-butane which is a rather expensive J E C 01 Oldrich Nem Prague and 5 starting material. Further, in many cases the alkylation 05 tvflfllk, omouc, a i does not run smoothly.

Jifi Mayer l 3 51 Our present invention consists in reacting halogenated fauna g g f ze 0s ova a unsaturated hydrocarbons having at least one halogen company 0 zec 05 ov a atom on a single bond carbon atom and at least one halo- No Drawing. Application September 23, 1955, m gen atom on a double bond carbon atom, with a 1,2-di- Serial 536,276 aryl-3,5-dioxo pyrazolidine or with its malonic compoh l nent, and in treating the diaryl dioXo pyrazolidines thus Chums gg gg%gg g z 0S ovakm formed, substituted in the position 4 by a single halogenalkenyl group or by two such groups, with reducing agents 7 Claims. (Cl. 260-310) either immediately or after converting the halogenalkenyl pyrazolidines into their alkanonyl derivatives. This invention relates to a process for producing 4-sub- The process of our invention may be illustrated by the stituted 1,2-diaryl-3,5-dioxo pyrazolidines, especially the 4- following schema in which R is alkyl and R is aryl:

R.oo1=on.oH,3 1: 'r' /GONR R.oo1=o11.cH=1 '1 'f oofojiejjr't'uvn' O l O a co NR' H/ GOl (TIY fi'lNR' Xi R.COI=OH.CH: (Jo-NR v H O0NR' z i 3.05 0305, /GONR' R.CO.CH2.CH: CO-NR H CONR H CO-NR' ROHLOHLOHQ (JO-NR i H/ \VOONR alkylated and 4-alkenylated derivatives of the referred to Some examples of the polyhalogenated alkenes which lidine have been found to be suitable for the purpose of this The primary object of our invention is to provide a invention are l,3-dichlorobutene-2, 1,3-dichloroheXadinew process for the production of 4-substituted 1,2-dicue-3,5, and trichlorohexenes. All these compounds may aryl-3,5-dioxo pyrazolidines. More specific objects of the easily be prepared from waste products of the chloroprene present invention center about the preparation of the 4- manufacture. 1,3-dichlorobutene-2 is formed as a secalkylated, 4-alkenylated, 4,4-dialky1ated, and 4,4-dialken-' ondary product during the addition of hydrochloric acid ylated derivatives. Further objects of the invention will to monovinylacetylene. 1,3-dichlorohexadiene-3,5 and become apparent from the following description. trichlorohexenes may be obtained by hydrochloration of The alkyl derivatives of the aforesaid pyrazolidines divinylacetylene which is a secondary product of the have been p epar Until now y Condensing Substituted monovinylacetylene synthesis from acetylene. Said polymalonic acid esters with 1,2-diary1hydrazines, or by alkylhalogenated alkenes and dienes are not only inexpensive ating 1,2-diaryl-3,5-dioxo pyrazolidines having at least but also more reactive than simple halogenalkanes, so one free hydrogen atom in the position 4. The nonthat the halogenalkenylation can more readily be carried alkylated diaryl dioxo pyrazolidines, serving as starting out than the usual alkylation. The reduction offers no materials, have been prepared by condensing non-substidifficulties and the yield of the process is relatively high. tuted malonic acid esters with 1,2-diaryl hydrazines, e. g. The most important of the polyhalogenated unsaturated hydrazobenzene. The 4-cycloalkylated diaryl dioxo pyhydrocarbons, suitable for the purpose of this invention, razolidines may be prepared by condensing a cyclic ke- 5 is 1,3-dichlorobutene-2; it is, as has been stated, easy to tone with l,2-d.iaryl-3,S-dioxo pyrazolidine having no subprepare from the waste material of the chloroprene manustituent in the 4-position. First, a cycloalkylidene derivafacture and may be converted without appreciable diffitive forms, which is then hydrogenated in order to remove culties into the valuable 4-butyl-l,2-diphenyl-3,5-dioxo the double bond between the pyrazolidine nucleus and the pyrazolidine.

cycloalkyl radical. The most important of these prod The selective reduction or hydrogenation of the haloucts is the 4-n-butyl derivative which shows excellent genalkenyl pyrazolidines may be carried out either by analgetic, antipyretic, and antirheumatic properties. This splitting ofi the halogen atom only, whereby the double bond remains unchanged, or'by converting the double bond into a single bond. In the first case, a 4-alkenyl diaryl dioxo pyrazolidine is built, whereas in the second case, a 4-alkyl derivative is obtained. The selective splitting oil of the halogen atom only may be accomplished, for instance, by hydrogenation, using a palladium catalyst at room temperature under atmospheric pressure. Under conventional hydrogenation conditions, using c. g. R'aney nickel and increased temperature and/orpressurefithlecorresponding aLkyl derivative isobtained.

. The reduction may be accomplished without introducing gaseous hydrogen. Instead, solid or liquid reducing agents may be used, e. g. sodium or its compounds, such as a sodium alcoholate, aluminum or its alloys in an alkaline aqueous medium, etc. Whenusing sodium alcoholate, a '4-alkenyl derivative results. .The use of aluminum in an alkaline:aqueous mediutn leads to 4-alkyl derivatives. The reductionbf 4 a lkanonylderivatives may be accomplished by the usual ste'ps of-removing anoxo group.

The present invention is illustrated by the following examples which, however, donotlimit the =scofpe of the invention:

Example 1 24.8 weight parts of 1-,2-diphenyl-3,5-dioxo pyrazolidine are dissolved'in'analkaline lye, containing an equivalent amount of NaOH. Into this solution, 12.5 'parts of 1,3-dichlorobutene-2 are slowly dropwise introduced, while stirring. After the addition, the mixture is stirred for more minutes at 50 C. The mixture is then cooled and shaken out with benzene or with another solvent, immiscible With water. Theaque'ous'layer formed, containing the sodium salt of the gamma-chloroalkenylated pyrazolidine derivative, is separated, decolorized by means of activated charcoal, and acidified until a definite acid reaction on Congo-red paper is achieved; The 1,2 diphenyl 3,5 dioxo 4 gamma chloro crotyl pyrazolidine thus obtained forms, "after purification by recrystallization from aqueous ethanol and acetone, respectively, colorless needles melting at 167-169 C. (corri).

5 parts of said chlorocrotyl derivative are dissolved in an alkaline lye, preparedfrom 200 parts of water and 2 parts of sodiumhydr'o'xide. Thereafter, one part of Raney nickel is added. The mixture is hydrogenated at atmospheric pressure until the theoretical amount of hydrogen is consumed. Upon completion of the reaction, the catalyst is removed by filtra'ti'o'n under Suction, from the obtained aqueous solution of its s'odium salt,-'f he- 4-n-buty l- 1,2-'diphenyl-3,5-diox'o pyra'z'olidine is precipitated by acidification. The pure product -"melts "at 105 f C.

Example :2

24.8 parts of gamma-chlorocrotyl malonic acid diethyl ester, obtained by condensing malonic acid diethylies'ter with 1,3-dichlorobuten e-2, are poured into a solution of 2.53 parts of sodium-and 18.41parts of hydrazobenzene in 65 parts of absolute ethanol. The mixture is gradually heated'to its boilingepoint, whereby'the ethanol is simultaneously removed by distillation. The temperature rises gradually, and after 5 hours 'thecondensation is finished. The mixture is diluted with 100 parts of water and treated according to Example 1.

5' parts of -4-gamma-chlor'ocrotyl--1,2@diphenyl13,5-dioxo pyrazolidine'are dissolved in'500 parts of ethanol; After adding 0.5 of palladium catalyst, precipitated on calcium carbonate, the mixture is hydrogenated under atmospheric pressure until the theoretical consumption of hydrogen is achieved, corresponding to the removal of the'chlorine on the double bond. Ethanol'is then distilled off. The

residue is'diss'olved'in'a diluted alkaline 'lye and filtered. The filtrate is precipitated by adding'hydrochloric acid, and the precipitate is sucked off. The 4-butenyl(2)-1,2-

diphenyl-3,5-dioxo pyrazolidine, purified by recrystallization, melts at 128 C.

Example 3 A solution of 4.84 parts of sodium in 120 parts of waterfree ethanol is added, drop by drop, to a mixture of 18.4 parts of hydrazobenzene, 16 parts of diethyl ester of malonic acid, and 12.5 parts of 1,3-dichlorobutene-2.

The temperature is kept at"70 C. After the addition of the sodium ethylate, the mixture is kept boiling for 1 hour under reflux. Then, the ethanol is distilled-off. The mashed residue is diluted with Water and treated according to Example 1. 1 part "of :the compound obtained, which is identical with the '4-gamma-chl'orocrotyl derivative obtained according to Example '1 or 2, is dissolved in 15 parts of dioxane and 50 parts of n butanol on a waterbath. 'Th'en,2 parts of sodium are gradually'thrown in during half an hour. After completion of the reaction, the mixture is cooled, 75;.parts of water are added, and the mixture is extracted with benzene. 'The water layer is precipitated with concentrated hydrochloric acid, and the precipitate sucked off. After purification by recrystallization, 4-butenyl(2)-1,2-diphenyl-3,5-dioxo pyrazoli: dine, obtained inform of needlelike crystals, 'me'lts at 128 'C. I

' Example 4 5 .parts of the 4-gamma-chlorocrotyl-l,2-diphenyl3,5-

dioxo pyrazolidine, obtained according to Example 1, are

dissolved in an alkaline lye, prepared by dissolving 25 parts of sodium hydroxide in 150 parts of water. 6 parts of powdered aluminum-nickel alloy (Raney alloy) are added in the course of 40 minutes at 70 C. After cooling, the separated nickel is removed by filtration and Washed repeatedly with diluted sodium lye.- The filtrate together with the washing liquid is precipitated with concentrated hydrochloric acid. The precipitate is sucked off, dissolved by boiling with excessive methanol, and freed from inorganic impurities by filtration. The hot filtrate is precipitated by adding water. Crystallized 4-n-butyl-1,2-

diphenyl-3,5-dioxo pyrazolidine, melting at 105 C., is separated.

Example 5 .iposing -'the intermediate :product with water.

7.5 parts of said 4-butanonyl(2)-1,2-diphenyl3 ,5'di- 'oxo'pyrazolidine are mixed with '70 parts of methylene glycol, 7 parts of potassium hydroxide, and v5 ,parts of hydrazine hydrate (almost The mixture is heated for 1 hour under irefiux. Then the reflux-cooler is replaced by a usual one, and the-solvent isdistilled off. During the distillation, the-temperature 'risessgradually to :195-'-200 C. 'and is kept at-this level-for 4 more hours. After cooling, the mixture is poured into 500 parts of water-and extracted three times with=250 parts of benzene. The aqueous portion -is decolorized by means of activated charcoal and precipitated with hydrochloric acid. The 4-- n-'- butyl- '1,2'- diphenyl 3,5- dioxo pyrazolidine, obtained in this way, -melts after purification by recrystallization at C.

Instead of a single substituted 1,2-Idiphenyl-.3,5-dioxo pymz'olidi ne, double substituted derivatives:may be prepared as well. For'this purpose, the corresponding bishalogen-alkenyl derivatives. -may be used, 'e. g. the bis- (gamma-clilorocr'otyl) -malonic aciddiet-hyl ester or the corresponding pyrazolidine, obtained therefrom by the above described vmethod, bearing two 'halogenalkenyl radicals "on the 4'-carbon atom.

'We claim: "Llrocess forsproducing 4=substituted 1.1,2-diphenyl- 3,5-dioxo pyrazolidines, comprising heating, in an alka- 2,77s,sao

line medium, 1,3-dichlorobutene-2 with a compound selected from the group consisting of 1,2-diphenyl-3,5- dioxo pyrazolidine and its malonic component, and treating the obtained diphenyl dioxo pyrazolidine, substituted in the 4-position by at least a single gamma-chlorocrotyl group, with reducing agents.

2. Process for producing 4-n-butenyl-1,2-diphenyl-3, S-dioxo-pyrazolidine, comprising heating, in an alkaline medium, 1,3-dichlorobutene-2 with a compound selected from the group consisting of 1,2-diphenyl-3,5-dioxo pyrazolidine and its malonic component, and treating the obtained 4 gamma chlorocrotyl 1,2 diphenyl 3,5- dioxo pyrazolidine with hydrogen at temperatures between about and 50 C. in the presence of a palladium catalyst under atmospheric pressure.

3. Process for producing 4 n butenyl 1,2 diphenyl 3,5 dioxo pyrazolidine, comprising heating, in an alkaline medium, 1,3-dichlorobutene-2 with a compound selected from the group consisting of 1,2-diphenyl- 3,5-dioxo pyrazolidine and its malonic component, and treating the obtained 4 gamma chlorocrotyl 1,2 dip-heny1-3,5-dioxo pyrazolidine with sodium in an alcoholic solution.

4. Process of producing 4 n butyl 1,2 diphenyl- 3,5-dioxo pyrazolidine, comprising heating, in an alkaiine medium, 1,3-dichlorobutene-2 with a compound selected from the group consisting of 1,2-diphenyl-3,5- dioxo pyrazolidine and its malonic component, and treating the obtained 4 gamma chlorocrotyl 1,2 diphenyl-3,5-dioxo pyrazolidine in an alkaline aqueous medium with a reducing agent selected from the group consisting of aluminum and an aluminum-nickel alloy.

5. Process of producing 4 n butyl 1,2 diphenyl- 3,5-dioxo pyrazolidine, comprising heating, in an alkaline medium, l,3-dichlorobutene-2 with a compound selected from the group consisting of 1,2-diphenyl-3,5-di- 0x0 pyrazolidine and its malonic component, treating the obtained 4 gamma chlorocrotyl 1,2 diphenyl 3,5- dioxo pyrazolidine with hydrogen in the presence of R-aney nickel in an aqueous alkaline solution, and precipitating the desired product by acidification.

6. Process of producing 4 n butyl 1,2 diphenyl-3,5-dioxo pyrazolidine, comprising heating, in an alkaline medium, 1,3-dichlorobutene-2 with a compound selected from the group consisting of 1,2-diphenyl-3,5- dioxo pyrazolidine and its malonic component, treating the obtained 4 gamma chlorocrotyl 1,2 diphenyl- 3,5-dioxo pyrazolidine with concentrated sulphuric acid until gaseous hydrogen chloride ceases to escape, decomposing the intermediate product with water, and treating the thus obtained 4-butauonyl(2)-1,2-diphenyl-3,5-dioxo pyrazolidine with reducing agents.

' 7. Process for producing 4-n-butyl-1,2diphenyl-3,5- dioxo pyrazolidine comp-rising heating a compound selected from the group consisting of malonic acid and 'its reactive derivatives with hydrazobenzene and 1,3-dichlorobutene-Z under gradual addition of a sodium alcoh-olate, isolating the 4-gamma-chlorocrotyl-1,2-diphenyl- 3,5-dioxo pyrazolidine thus formed, and treating the latter with hydrogen in the presence of a catalyst.

Stenzl July 31, 1951 Hafliger Ian. 25, 1955 

1. PROCESS FOR PRODUCING 4-SUBSTITUTED 1,2-DIPHENYL3,5-DIOXO PYRAZOLIDINES, COMPRISING HEATING, IN AN ALKALINE MEDIUM, 1,3-DICHLOROBUTENE-2 WITH A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1,2-DIPHENYL-3,5DIOXO PYRAZOLIDINE AND ITS MALONIC COMPONENT, AND TREATING THE OBTAINED DIPHENYL DIOXO PYRAZOLIDINE, SUBSTITUTED IN THE 4-POSITION BY AT LEAST A SINGLE GRAMMA-CHLOROCROTYL GROUP, WITH REDUCING AGENTS. 